Mevacor.
MEVACOR (Lovastatin) is a cholesterol lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding Beta-hydroxacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3- menthylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol. The involvement of low-density lipoprotein (LDL) cholesterol in atherogenesis has been well- documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological studies have established that (high density lipoprotein) cholesterol are both risk factors for coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), coordinated by the National Institutes of Health (NIH) studied men aged 35-59 with total cholesterol levels 265mg/dL (6.8 mmol/L) or greater and triglyceride levels not more than 300 mg/dL (3.4 mmol/L). This seven-year, double-blind, placebo-controlled study demonstrated that lowering LDL cholesterol with diet and cholestyamine decreased the combined rate of coronary heart disease death plus non-fatal myocardial infarction. Â
MEVACOR has been shown to reduce both normal and elevated LDL cholesterol concentrations. LDL is formed from VDL and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of MEVACOR may involve both reduction of VLDL cholesterol concentration, and induction of the LDL receptor; leading to reduced production and/or increased catabolism of LDL cholesterol. Apolipoprotein B also falls substantially during treatment with MEVACOR. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that MEVACOR does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, MEVACOR can produce increases of variable magnitude in HDL cholesterol, and modestly reduces VLDL cholesterol and plasma triglycerides (see Tables I-IV under Clinical Studies). The effects of MEVACOR or Lp(a) fibrinogen, and certain other independant biochemical risk markers for coronary heart disease are unknown. Â
MEVACOR is a specific inhibitor of HMG-CoA to mevalonate. The conversation of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding B-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the B-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
 Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radio activity (lovastatin plus 14C- metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in nontarget tissues. Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of hepatic extraction of lavastatin, the availability of drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of lovastatin tablets the coefficient of varation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation. Â
Both lovastatin and its B-hydroxyacid metabolite are highly bound (95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers. Â
The major active metabolites present in human plasma are the B-hydroxyacid of lovastatin, its 6- hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing lovastatin tablet-dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the second and third days of therapy and were about 1.5 times those following a single dose. When lovastatin was given under fasting condition, plasma concentrations of total inhibitors were on average about two- thirds those found when lovastatin was administered immediately after a standard test meal. Â
In a study of patients with severe insufficiency (creatinine clearance 10-30 mL/min) , the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
MEVACOR has been shown to be highly effective in reducing total LDL cholesterol in the heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night. In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia, MEVACOR administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d. was compared to placebo. MEVACOR consistently and significantly decreased total plasma cholesterol (TOTAL- C), LDL cholesterol (LDL-C), total cholesterol/HDL cholesterol (TOTAL-C/HDL) ratio and LDL cholesterol/HDL-C) ratio. In addition, MEVACOR produced increases of variable magnitude in HDL cholesterol (HDL-C), and modestly decreased VLDL cholesterol (VLDL-C) and plasma triglycerides (TRIG). (see Tables I through IV for dose response results).